Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression. They play a role in controlling expression of proteins that regulate lipid metabolism. Furthermore, the PPARs are activated by fatty acids and fatty acid metabolites. Three PPAR subtypes have been isolated: PPARα, PPARβ (also referred to as  or NUC1), and PPARγ. Each receptor shows a different pattern of gene expression by binding to DNA sequence elements, termed PPAR response elements (PPRE). In addition, each receptor show a difference in activation by structurally diverse compounds. To date, PPREs have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (Keller, H. and Wahli, W. Trends Endoodn. Met. 4:291-296 (1993).
PPARα is found in the liver, heart, kidney, muscle, brown adipose tissue and gut and is involved in stimulating β-oxidation of fatty acids. PPARα is also involved in the control of cholesterol levels in rodents and in humans. Fibrates are weak PPARα agonists that are effective in the treatment of lipid disorders. In humans, they have been shown to lower plasma triglycerides and LDL cholesterol. In addition, PPARα agonists have also been reported to prevent diabetes and to improve insulin sensitivity and reduce adiposity in obese and diabetic rodents (see Koh, E. H. et al. Diabetes 52:2331-2337 (2003); and Guerre-Millo, M. et al. J. Biol. Chem. 275: 16638-16642 (2000)).
PPARβ is ubiquitously expressed. Activation of PPARβ increases HDL levels in rodents and monkeys (see Oliver, W. R. et al. PNAS 98:5306-5311 (2001); and Leibowitz, M. D. et al. FEBS Letters 473:333-336 (2000)). Moreover, PPARβ has been recently shown to be a key regulator of lipid catabolism and energy uncoupling in skeletal muscle cells (Dressel, U. et al. Mol Endocrinol. 17: 2477-2493 (2003)). In rodents, activation of PPARβ induces fatty β-oxidation in skeletal muscle and adipose tissue, leading to protection against diet-induced obesity and diabetes (see Wang, Y. X. et al. Cell 113:159-170 (2003); and Tanaka et al. PNAS 100:15924-15929 (2003)). In human macrophages, PPARβ activation also increases the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux (see Oliver, W. R. et al. PNAS 98:5306-5311 (2001)).
PPARγ is expressed most abundantly in adipose tissue and induces adipocyte differentiation. Drugs of the thiazolidinedione (TZD) class namely troglitazone, pioglitazone, and rosiglitazone are potent and selective activators of PPARγ. In humans, these drugs increase insulin action, reduce serum glucose, induce the differentiation of preadipocytes to adipocytes, and have small but significant effects on reducing serum triglyceride levels in patients with type 2 diabetes. These agents have also been implicated in the regulation of triglyceride and cholesterol levels in humans or animal models (See, e.g., U.S. Pat. No. 5,859,501, and PCT publications WO 97/28149 and 99/04815). The role of PPARs in the regulation of metabolism has been the subject of a number of reviews (see, Spiegelman, Diabetes, Vol. 47, pp. 507-514 (1998); Schoonjans, et al., Curr. Opin. Lipidol. 8, 159-166 (1997); Brun, et al., Curr. Opin. Lipidol. 8: 212-218 (1997). More recently, the (−) isomers of halofenic acid which are particularly useful in the treatment of insulin resistance, Type II diabetes, obesity, and hyperuricemia (See, U.S. Pat. Nos. 6,646,004; 6,624,194; 6,613,802; and 6,262,118, each to Luskey et al.) have also been recently reported to be selective, partial PPARγ agonists.
The PPARγ receptor is found in many other tissues than adipose tissue. PPARγ modulators can have beneficial effects in many other diseases including cardiovascular disease, inflammation, and cancer. (Schoonjans et al, Curr. Opin. Lipidol. 8, 159-166 (1997); Ricote, et al., Nature 391: 79-82 (1998); Mueller, et al., Mol. Cell 1: 465-470 (1998)).
PPARγ activation induces growth arrest by terminal differentiation of actively proliferating PPARγ-expressing cells, including transformed adipose precursor cells. PPARγ is consistently and selectively expressed in each of the major histologic types of human liposarcoma compared to other soft tissue sarcomas and is also selectively expressed in human breast adenocarcinomas and advanced metastatic breast tumors (see WO 98/25598). PPARγ activators have been shown to induce differentiation of malignant liposarcoma cell lines to adopt a morphology characteristic of mature cultured adipocytes. PPARγ activators also have been shown to induce cell-cycle withdrawal in NIH3T3 cells transfected with PPARγ, in transformed brown adipocyte cell line HIB 1B, and in NIH-3T3-F442A preadipocytes. PPARγ modulators have also been found to reduce the size of adipose cell tumors (HIB 1B) in nude mice.
PPARγ is expressed in many human cancer cell lines and have been shown to inhibit the proliferation of leukemic cells, prostate cancer cells, and breast cancer cells (see PCT Patent Publication, WO 98/25598 and also U.S. Pat. No. 6,242,196 to Spiegelman). The activation of PPARγ by its natural and synthetic ligands has been reported to induce apoptosis in several tumor cell lines, including malignant B-lineage cells (Eucker et al., Anticancer Drugs 15(10):955-60 (2004)) and Waldenstrom's macroglobulinemia (Mitsiades et al., Semin Oncol. 30(2):309-12 (2003)). PPARγ agonists have also been reported to suppress liver carcinogenesis induced by diethylnitrosamine in rats (Guo et al., World J Gastroenterol. 0(23):3419-23 (2004)) and inhibit growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects (Yoshizumi et al., Int J Oncol. 25(3):631-9 (2004)). The ligands of PPARγ also been reported inhibit growth of human esophageal carcinoma cells through induction of apoptosis and cell cycle arrest (Fujii et al., Anticancer Res. 24(3a): 1409-16 (2004)). PPARγ activation has also been reported to inhibit tumor progression in non-small-cell lung cancer. (Keshamouni et al., Oncogene 23(1):100-8 (2004)). In many instances, PPARγ therapy does not merely induce differentiation it induces apoptosis. Activation of PPARγ has such an effect on urological cancer cells (Yoshimura et al., Int J Mol Med. 12(6):861-5 (2003). PPARγ activators have also been reported to inhibit the growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway (Tsujie et al., Exp Cell Res. 289(1):143-51 (2003)). The use of PPARγ activators in the treatment of cancer is also disclosed in U.S. Pat. No. 6,294,559 to Smith et al. and U.S. Pat. No. 6,579,893 to Urban et al. and U.S. Patent Application Publication No. 20040162354 published on Aug. 19, 2004). The effects of PPARγ modulators on cell proliferation and cancer have also been observed for partial agonists such as troglitazone (see, U.S. Pat. No. 6,242,196) and U.S. Patent Application Publications Nos. 20040266834 and 20030032581.
More recently, the (−) isomers of halofenic acid and derivatives thereof which are particularly useful in the treatment of insulin resistance, Type II diabetes, obesity, and hyperuricemia (See, U.S. Pat. Nos. 6,646,004; 6,624,194; 6,613,802; and 6,262,118, each to Luskey et al. and also U.S. Patent Application Publication No. 20040029933 to Zhao et al.) have also been reported to be selective, partial PPARγ agonists with unexpectedly advantageous properties over their (+) isomers with respect to COX-1 inhibition, glucose lowering, and inhibition of Cytochrome P450 2C9. It has now been surprisingly found that these compounds are also useful in treating and preventing edema and the adverse health effects of edema.
PPARγ thus remains an important target for treating many hyperplastic and neoplastic disorders. However, what is needed in the art are new compounds and methods useful for modulating PPARγ in the treatment of hyperplastic and neoplastic disorders, including cancer, which avoid any such side effects of the PPARγ modulators while providing the benefits of PPARγ modulation in the treatment of these disorders. The present invention fulfills this and other needs by providing a selective, partial agonists of PPARγ with an improved side effect profile for use in treating these disorders.